Fluorine-containing compounds



States This invention relates to novel fluorine-containing compounds,particularly to 3-chloro-1,1,2,2-tetrafiuoropropane and3-bromo-1,1,2,2-tetrafluoropropane.

The compounds of this invention and a process for making them aredisclosed but not claimed in my copending application Serial No.808,900, filed April 27, 1959, now Patent No. 3,017,421, patentedJanuary 16, 1962, which discloses and claims polyfluoroalkyl chlorosulfonates, bis(polyfiuoroaikyl)sulfates and their preparation frompolyfluoroalkanols. Inhalation anesthetic mixtures containing the3-bromo-1,1,2,2-tetrafluoropropane of this invention as an anestheticare disclosed and claimed by Kenneth T Dishart in his copendingapplication Serial No. 834,941, filed August 20, 1959, now abandoned andreplaced by application Serial No. 95,501, filed March 14, 1961, andpatented May 15, 1962, asPatent No. 3,034,959.

It is known that a number of organic fluorine compounds have anestheticproperties. While some of these do not have the undesirable propertiesof the common inhalation anesthetics, nearly all of them have otherundesirable properties, such as high toxicity, hydrolytic instability,reactivity with soda-lime, insufiicient eilectiveness in reasonableconcentrations, insufiicient margin of safety, and most producingundesirable physiological side effects. B. H. Robbins in J. Pharmacologyand Experimental Therapeutics, 86, 197-204 (1946), reports the resultsof tests with some 46 fluorine compounds. Of these, only 18 wereconsidered to show sufficient promise to Warrant testing on other thanmice, and only 4 produced results such that it was felt that furtherinvesigations thereof were indicated.

One organic fluorine compound has been accepted as being suitable forclinical use as an inhalation anesthetic. Such compound is2-bromo-2-chloro-1,1,l-trifluoroethane which is sold under the tradename Fluothane. Such compound is a comparatively new, very potent,nonflammable anesthetic. The efiective concentration varies from about1% to less than 3.5% with surgical anesthesia being induced within 5 to7 minutes with concentrations of 2% to 2.5% and maintained withconcentrations of 0.8% to 1%. It is sold with the caution that it doesnot permit a wide margin of error, and sudden exposure to relativelyhigh concentrations can lead to profound hypotension with cardiacarrest, whereby the accurate and proper ad ministration of it ismandatory and it should be used only in Vaporizers that have beencalibrated accurately to permit concentrations that may be altered infractions of 0.1 percent over a clinical range of 0.5 percent to 3.5percent and under the control of a trained anesthetist. It is pointedout that during induction 2. short but definite excitement period isusually present unless premedication is administered, a diminution ofrespiratory exchange develops and usually persists, and hypotension ofvariable degree is common, according to the depth of anesthesia. Ingeneral, muscle relaxation adequate for major surgical procedures isobtained only at anesthetic levels where a hypotension of some severitymay occur.

It is an object of this invention to provide novel fluorinecontainingcompounds. A particular object is to provide3-chloro-1,1,2,2-tetrafiuoropropane and 3-bromo-1,l,2,2-tetrafiuoropropane, which have new and unusual properties. Other objectsare to advance the art. objects will appear hereinafter.

Still other atet 2 i The above and other objects may be accomplished inaccordance with this invention which comprises compounds of the formulaHCF CF CH X wherein X is a halogen having an atomic weight between 35and 80, i.e. 3-chloro-1,1,2,2-tetrafluoropropane having the formula HCFCF CI-I Cl and 3-bromo-1,1,2,2-tetrafiuoropropane having the formula HCFCF Cl-I Br.

The compounds of this invention are new compounds which are useful for awide variety of purposes. They are useful as solvents, heat exchangemedia, hydraulic fluids, dielectrics, fire extinguishing agents,intermediates for the manufacture of other fluorine-containingcompounds, and the like. The 3-bromo-1,1,2,2-tetrafiuoropropane isparticularly valuable as an inhalation anesthetic, and has unexpected-1yunique properties for that purpose as disclosed more fully by Dishart inPatent No. 3,034,959.

The compounds of this invention are nonexplosive and nonflammable inair, and are stable solvents for oils and greases but have little effecton elastomers, plastics, insulation materials and metals. A selectivesolvent action adapts them for removing oil, grease, and dirt from suchobjects and equipment as motor stators, electrical controls, optical andprecision instruments, gages, and aircraft instruments, without harm tometal or plastic parts. The compounds are preferably used as solvents inclosed systems or well ventilated areas. The compounds are also usefulas solvent media for the polymerization of pertluoroolefins, forexample, tetrafluoroethylene.

The bromoand chlorofluoropropanes of this invention may be used as lowboiling dielectric media to provide, for example, insulation and coolingsimultaneously through evaporation in equipment fitted with a refluxcondenser. The dielectric constants are:

Dielectric Constant, 8,000 cycles pre sec. at 25 0.

Compound S-bromo-1,1,2,2-tetralluoropropane In comparison, petroleum oilthat is widely used as a dielectric has a dielectric constant of about2, and highly chlorinated aromatic hydrocarbons that provide advantagesover petroleum oil as dielectrics have a dielectric constant of 5 to 6.

The compounds are effective fire extinguishing agents. For example, avigorous gasoline fire in an open dish was readily made to subside andto go out by impinging a fine stream of either the bromoor thechlorofluoropropane onto the burning gasoline. The fire of 'awellburning paper and wood-chip mixture was soon smothered and put outwith a stream of either compound. A temporary fire-proofing effect wasprovided, as the woodchips absorbed the fire extinguishing compound andcould not be immediately reignited.

It has been found that the 3-brorno-l,1,2,2-tetrafiuoropropane of thisinvention is especially well adapted for use as an inhalation anestheticbecause it smoothly and readily induces a deep anesthesia and itsvapors, in concentrations within the anesthetic range, have a pleasantand non-irritating odor. This compound is nonfiammable and its vapors,mixed with oxygen in the proportions used for anesthesia, is notflammable or explosive. In concentrations that produce anesthesiasatisfactory for surgical purposes, the compound does not causeconvulsions in mice and dogs. It may be administered by various machinetechniques with a wide margin of safety and has been observed to produceno pronounced change in respiratory rate or blood pressure in dogs untilvery deep levels of anesthesia were reached and maintained.

tion of from about 6% to about 7% by volume in oxy-' gen or air inducesa surgical depth of anesthesia in dogs. Such level is readily maintainedwith concentrations of from about 4% to about by volume. Concentrationsin excess of 8% have been used without fatality. At a given level ofanesthesia in dogs, blood pressure depression is generally low.

The compounds of this invention may be considered to be members ofseries of compounds, the members of which differ firom the adjacentmembers by a -CF group, which series may be represented by the formulaeH(-CF CH CI and H(CF CH Br wherein n represents an integer. Not allmembers of each series are known. Of those that are known, none, otherthan the 3-bromcl,l,2,2-tetrafiuoropropane of this invention, has beenfound suitable as an inhalation anesthetic. For example,

the compounds of the formula H(CF CH CI and H(CF CH Br cause convulsionsin mice when used in inhalation anesthetic mixtures. The compounds inwhich n is 6 or higher have too low a vapor pressure at ordinary roomtemperatures to function as inhalation anesthetics.2-bromo-1,l-difiuoroethane (n=1) having the formula HCF CI-I Br isunsuitable as an inhalation anesthetic because, when it was so used ondogs, it rendered them rigid, produced convulsions and resulted incardiac arrhythmia as disclosed by Robbins in J. Pharmacology andExperimental Therapeutics, 86, pp. 197-204 (1946), see particularly page202.

Robbins (10c. cit.) tested 2-chloro-1,1 difiuorcethane (11:1) having theformula HCF CH CI as an inhalation anesthetic on mice and found that ithad an AD 50 value (the dose in volume percent in an air atmosphererequired to induce anesthesia in 50% of the mice upon ten minutesexposure) of 2.15% and an FD value (the dose in volume percent thatcaused death in 50% of the mice in ten minutes) of 7.5 (page 198), butdid not consider it to show .sufiicient promise to warrant testing itwith dogs or other animals. On the other hand, as shown by Dishart inPatent No. 3,034,959, 3-bromo-1,1,2,2-tetrafiuoropropane has an AD 50-value in mice of 0.5%. Thus, the anesthetic dose (AD) of HCF CH CI ismore than 4 times that for 3-bromo-1,1,2,2-tetrafiuoropropane.

A convenient method for preparing the compounds of 'this invention is toform a p-toluenesulfonic acid ester of 2,2,3,3-tetrafluoro-1-propanolfollowing the procedure of Tiers et a1. (JACS, 75, 5978 (1953)) and thento react the resultant ester with the appropriate potassium halide toyield 3-bromo-( or 3-chloro-) l,1,2,2-tetrafiuoropropane following theprocedure of Faurote et al. (IACS, 78, 4999 (1956)). Another method ofpreparation is to react the sodium derivative of 2,2,3,3-tetrafluoro-1-propancl with sulfuryl chloride and to convert the resultantchl-oro-sulfonate or sulfate ester to the required chloroorbromo-tetrailuor=opropane by reaction With lithium halide. A directmethod for preparing the 3- chloro-l,1,2,2-tetratfiuoropropane is tofeed 2,2,3,3-tetrafluoro-l-propanol to a refluxing mixture of thionylchloride and pyridine, continue the refluxing, and then distill the3-chloro-1,1,2,24etrafiuoropropane from the reaction mixture.

In order to more clearlyillustrate the preparation of the compounds ofthis invention, the following examples are given in which theproportions are by weight except where it is specifically indicatedotherwise.

EXAMPLE 1 Preparation of 2,2,3,3-Tetrafluoropropyl ChlorosulfonateSulfuryl chloride (168.5 g., 1.25 mol), dissolved in2,2,3,3-tetrafiuoro-1prop anol (132 g., 1 mol), was added dropwise at 45C.65 C. to a solution prepared by reacting sodium wire (23 g., 1 mol)with 2,2,3,3-tetrafluoro-1- propanol (330 g., 2.5 mol) At the end ofone-half hours stirring, the solution was acidic. The reaction mixturewas filtered to remove sodium chloride, and the filtrate was distilled.The fraction distilling at 142 C. to 145 C. (127.5 g.) was the desired2,2,3,3-tetrafiuoropropyl chlorosulfonate and had an index of refraction(11 of 1.3710.

Analysis.-Calculated for C H O SF CI: C, 15.61; S, 13.87; Cl, 15.39.Found: C, 15.55; S, 13.5; C1, 15.25.

Conversion to 3 -Chlor0-1 ,1 ,2,2 -Tetraflu0r0pr0pane Lithium chloride(25.4 g., 0.6 mol) was heated in 75 nil. of diethylene glycol to 125 C.in a flask fitted with a Water separator-condenser unit. 2,2,3,3tetrafluoropropyl chlorosulfonate (58 g., 0.25 mol) was added drop- WiseWhile stirring the reaction mixture. The product began to distill at thestart of addition and continued to distill throughout the reaction. Thepot temperature was raised to 170 C. before cooling. The crudedistillate, collecting in the water separator, Weighed 33 g. After beingwashed with ice water, drying over anhydrous MgSO and distilling, 3-chloro-1,1,2,2 -tetrafluoropropane was obtained in 61% yield (23 g.).By further fractional distillation and passage through columns ofalumina activated by heating in an air oven at 200 C. for four days, ahigh quality compound was provided. Its physical properties and theresult of chemical analysis are: M.P. -110 C., B.P. at 760 mm. 55 C.,sp. gr. 20/4=1.43, n 1.3218; calculated chlorine content 23.58%, found23.4% C1.

EXAMPLE 2 Preparation of Bis(2,2,3,3-Tetrafluoropr0pyl)Sulfate SodiumWire (23 g., 1 mol) was reacted at C.-95 C. in excess2,2,3,3-tetrafiuoro-1-propanol (330 g., 2.5 mol). To this solution,sulfuryl chloride (67.5 g., 0.5 mol), dissolved in2,2,3,3-tetrafluoro-l-propanol (132 g., 1 mol), was added slowly at 70C.- C. A white precipitate of sodium chloride formed. After'standing forabout 48 hours at room temperature, the strongly acidic mixture wasfiltered to remove the salt. The filtrate was distilled at 107 C.112 C.to remove unreacted fluoro-alkanol. The residue from the firstdistillation consisted of two immiscible phases which were thenfractionally distilled under vacuum. The desiredbis(2,2,3,3-tetratluoropropy1)sulfate distills at C. to 91 C./6 mm.(61.5 g.); n 1.3498.

Analysis. Calculated for C H O SF C, 22.1; H, 1.84; F, 46.62; S, 9.81.Found: C, 22.7; H, 2.1; F, 45.1; S, 9.9.

Conversion to 3-Br0m0-1,1,2,2-Tetrafluoropr0pane Lithium bromide (14.5g., 0.167 mol) and bis(2,2,3,3- tetrafiuoropropyhsulfate (27.5 g., 0.083mol) were heated in 50 ml. diethylene glycol in a flask fitted with awater separator-condenser unit. The product began to distill when themixture reached C. and continued to come over as the reactiontemperature rose. The pot temperature was raised to C. before cooling.The crude distillate, collecting in the water separator, weighed 15.5 g.After being washed twice with ice water, drying over anhydrous MgSOfractionally distilling, and passing through columns of alumina as inExample 1, pure 3- bromo-l,1,2,2-tetrafluoropropane was obtained. Itsphysical properties and the result of chemical analysis are: M.P. 70 C.,HP. at 760 mm. 74 C., sp. gr. 20/4=1.81, 11 1.3558; calculated brominecontent 41.01%, found 40.3% bromine.

EXAMPLE '3 Preparation of 2,2,3,3-Tetrafluoropropyl p-Toluenesulfonateovernight. The resultant mass was then poured into a mixture of ice andsodium bicarbonate. The ester crystallized and Was collected byfiltration. The ester was then dissolved in methanol, dried overanhydrous magnesium sulfate and filtered. The methanol was removed fromthe filtered solution by distillation at atmospheric pressure, and 142g. of the desired ester collected as distillate at 124 C. to 126 C. at 2mm. mercury pressure. The ester melts at 14 C. to 16 C., has n =L4600and sp. gr. 20/4=1.397.

Analysis.Calculated for C H F O S: C, 42.15; H, 3.5; F, 26.6; S, 11.2.Found: C, 41.9; H, 3.6; F, 26.0; S, 11.2.

Conversion to 3-Br0m0-1,1,2,2-Tetrafluoropropane By the procedure ofTiers et al. (IACS, 75, 5979, (1953)), 142.8 g. (0.5 mol) of the above2,2,3,3-tetrafiuoropropyl p-toluenesulfonate, 43.4 g. (0.5 mol) oflithium bromide and 150 ml. of diethylene glycol were heated togetherwith a rise of temperature to 190 C. over a period of 2 hours. Anadditional 9 g. portion of lithium bromide was added and the mass keptat about 190 C. for another 6 hours. A total of 90 g. of productdistilled from the reaction mass and was collected. The product waswashed twice with water, dried over anhydrous magnesium sulfate,fractionally distilled, and passed through columns of activated alumina.The final product had a boiling point of 74 C. at 760 mm., sp. gr. 20/4of 1.81, and refractive index 11;, of 1.3558.

thetic.

It will be understood that the foregoing examples are given forillustrative purposes solely and that this invention is not limited tothe specific embodiments described therein. On the other hand, it willbe apparent to those skilled in the art that variations andmodifications can be made therein, particularly in the materials,proportions and conditions employed without departing from the spiritand scope of this invention.

From all of the above, it will be apparent that this invention providesnovel compounds which are valuable for a variety of purposes.Particularly, the 3-bromo- 1,1,2,2-tetrafiuoropropane has unexpectedlyunique propert-ies whereby it is outstanding as an inhalation anes-Therefore, this invention constitutes a valuable advance in andcontribution to the art.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A fluorine-containing compound having [the formula HCF CF CH Xwherein X represents a halogen atom having an atomic weight between and80.

2. 3-chloro-l,1,2,2-tetrafiuoropropane.

3. 3-bromo-1,1,2,2-tetrafluoropropane.

References Cited in the file of this patent Henne et al.: J.A.C.S., 59,2363 (1943). Tarrant et al.: J.A.C.S., vol. 77, pp. 27837 (page 2785particularly relied on), 1955.

1. A FLUORINE-CINTAINING COMPOUND HAVING THE FORMULA HCF2CF2CH2X WHEREINX REPRESENTS A HALOGEN ATOM HAVING AN ATOMIC WEIGHT BETWEEN 35 AND 80.